Antiestrogens are pro-apoptotic in normal human breast epithelial cells

Int J Cancer. 2003 Jul 10;105(5):607-12. doi: 10.1002/ijc.11147.


Estrogens promote cell proliferation in normal and transformed mammary epithelial cells by inducing expression of hormone-responsive genes involved in the cell cycle. The action of antiestrogens is therefore central in regard to their potent inhibitory effects on estrogen-induced cell growth. We used normal human epithelial breast cells from primary cultures (HBE cells) to study hormonal (estrogen and antiestrogen) regulation on 3 key proteins involved in the apoptotic process: Bcl-2, p53 and caspase-3. The mammary adenocarcinoma cell line, MCF-7, was also used to study the molecular regulation of Bcl-2. In both HBE and MCF-7 cells, we found that estradiol (E2) induced an increase in Bcl-2 mRNA levels. This effect was counteracted in the presence of a pure antiestrogen, ICI 182780 (ICI). Alone, ICI did not modify either the Bcl-2 protein or mRNA levels in HBE cells, whereas in MCF-7, a strong downregulation of Bcl-2 mRNA was observed. In parallel, in HBE cells, we observed that E2 caused a decrease in p53 and caspase-3 protein levels, whereas ICI alone increased p53 and caspase-3 protein levels. The ICI effects on p53 and caspase-3 were partially counteracted by E2. Under the same experimental conditions, ICI exerts a potent pro-apoptotic effect, which was not counteracted by E2. In contrast, 4-hydroxytamoxifen was slightly weaker as a pro-apoptotic agent in HBE cells and its effects were reversed by E2. We demonstrate that in HBE cells, ICI reverses the anti-apoptotic action of E2 and alone acts as a highly potent pro-apoptotic molecule. These results provide new insight into treatment for breast cancer prevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis / drug effects*
  • Breast / cytology
  • Breast / drug effects*
  • Breast / metabolism
  • Breast Neoplasms / pathology
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / genetics
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Enzyme Induction / drug effects
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology*
  • Estrogen Receptor Modulators / pharmacology
  • Estrogens
  • Female
  • Fulvestrant
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, bcl-2
  • Genes, p53
  • Humans
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasms, Hormone-Dependent / pathology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Stimulation, Chemical
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Suppressor Protein p53 / biosynthesis


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor Modulators
  • Estrogens
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • RNA, Neoplasm
  • Tumor Suppressor Protein p53
  • Tamoxifen
  • afimoxifene
  • Fulvestrant
  • Estradiol
  • CASP3 protein, human
  • Caspase 3
  • Caspases